Albendazole ameliorates aerobic glycolysis in myofibroblasts to reverse pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disorder for which effective treatments remain limited. Recent investigations revealed a potential link between altered glucose metabolism and the activation of fibroblasts, the key cells responsible for generating and depositing extracellular matrix proteins within the lung interstitium during IPF development. METHOD: In this study, we aimed to investigate the potential therapeutic impact of albendazole on fibroblast to myofibroblast transition in IPF. We assess albendazole's effectiveness in attenuating the activation of fibroblasts. We focused on elucidating the mechanism underlying albendazole's impact on TGF-ß1-induced aerobic glycolysis in both lung tissues and fibroblasts obtained from patients with IPF and other lung fibrosis types. Furthermore, the antifibrotic effects of oral administration of albendazole were investigated in mouse models of pulmonary fibrosis induced by BLM or SiO2. Human precision-cut lung slices were employed to evaluate the impact of albendazole following TGF-ß1 stimulation. RESULT: In this work, we demonstrated that albendazole, a first-line broad-spectrum anthelmintic drug, effectively attenuated fibroblast to myofibroblast transition through alleviating TGF-ß1-induced aerobic glycolysis dependent on the LRRN3/PFKFB3 signaling pathway. Additionally, LRRN3 expression was downregulated in both lung tissues and fibroblasts from patients with IPF and other types of lung fibrosis. Importantly, the levels of LRRN3 correlated with the progression of the disease. Notably, oral administration of albendazole exerted potent antifibrotic effects in mouse models of pulmonary fibrosis induced by BLM or SiO2, and in human precision-cut lung slices after TGF-ß1 stimulation, as evidenced by improvements in lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1 and Fibronectin expression in the lungs. CONCLUSION: Our study implies that albendazole can act as a potent agonist of LRRN3 during fibroblast to myofibroblast differentiation and its oral administration shows potential as a viable therapeutic approach for managing IPF.

A disproportionality analysis of sunitinib in the FDA adverse event reporting system (FAERS).

Objective: This study aimed to analyze the FAERS database to identify adverse event associated with sunitinib to offer valuable insights for the judicious utilization of medication in clinical settings. Methods: Various disproportionality analysis techniques, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPN), and multi-gamma Poisson shrinkage (MGPS), were employed to analyze adverse drug reaction (ADR) reports pertaining to sunitinib in the FAERS database from its market introduction up to the first quarter of 2023. Subsequently, a secondary screening process was conducted to identify reliable positive signals. Results: The analysis of sunitinib adverse event signals at the system-organ classification level encompassed 27 organ systems, with gastrointestinal and endocrine disorders emerging as the predominant SOCs. A total of 237 significant adverse events meeting all four algorithms were detected. Notably, this study revealed previously unreported adverse events, including pleural effusion and ascites, while potential adrenal toxicity-related adverse events, highlighted in the drug's specification, were not identified in this analysis. The study examined the relationship between the duration of sunitinib dosing and the onset of adverse events, revealing a median onset of 48 days (IQR, 15-160 days). The findings indicated that a majority of adverse events manifested early in the dosing period, with tumor progression, disease progression, and mortality becoming more prevalent after one year of treatment. Conclusion: In the clinical utilization of sunitinib, vigilant monitoring of potential adverse reactions is imperative during the initial phase of drug administration. In addition to the documented adverse reactions outlined in the drug specification, healthcare providers should remain attentive to potential adverse reactions such as pleural effusion, ascites, and tumor development.

Regulation of myofibroblast dedifferentiation in pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a lethal, progressive, and irreversible condition that has become a significant focus of medical research due to its increasing incidence. This rising trend presents substantial challenges for patients, healthcare providers, and researchers. Despite the escalating burden of pulmonary fibrosis, the available therapeutic options remain limited. Currently, the United States Food and Drug Administration has approved two drugs for the treatment of pulmonary fibrosis-nintedanib and pirfenidone. However, their therapeutic effectiveness is limited, and they cannot reverse the fibrosis process. Additionally, these drugs are associated with significant side effects. Myofibroblasts play a central role in the pathophysiology of pulmonary fibrosis, significantly contributing to its progression. Consequently, strategies aimed at inhibiting myofibroblast differentiation or promoting their dedifferentiation hold promise as effective treatments. This review examines the regulation of myofibroblast dedifferentiation, exploring various signaling pathways, regulatory targets, and potential pharmaceutical interventions that could provide new directions for therapeutic development.

Acupuncture plus topiramate placebo versus topiramate plus sham acupuncture for the preventive treatment of chronic migraine: A single-blind, double-dummy, randomized controlled trial.

BACKGROUND: Acupuncture has been used for the treatment of chronic migraine, but high-quality evidence is scarce. We aimed to evaluate acupuncture's efficacy and safety compared to topiramate for chronic migraine. METHODS: This double-dummy randomized controlled trial included participants aged 18-65 years diagnosed with chronic migraine. They were randomly assigned (1:1) to receive acupuncture (three sessions/week) plus topiramate placebo (acupuncture group) or topiramate (50-100 mg/day) plus sham acupuncture (topiramate group) over 12 weeks, with the primary outcome being the mean change in monthly migraine days during weeks 1-12. RESULTS: Of 123 screened patients, 60 (mean age 45.8, 81.7% female) were randomly assigned to acupuncture or topiramate groups. Acupuncture demonstrated significantly greater reductions in monthly migraine days than topiramate (weeks 1-12: -2.79 [95% CI: -4.65 to -0.94, p = 0.004]; weeks 13-24: -3.25 [95% CI: -5.57 to -0.92, p = 0.007]). No severe adverse events were reported. CONCLUSIONS: Acupuncture may be safe and effective for treating chronic migraine. The efficacy of 12 weeks of acupuncture was sustained for 24 weeks and superior to that of topiramate. Acupuncture can be used as an optional preventive therapy for chronic migraine. TRIAL REGISTRATION: ISRCTN.org Identifier 13563102.

Effect of acupuncture for temporomandibular disorders: a randomized clinical trial.

BACKGROUND: Temporomandibular disorders (TMD) are the leading cause of pain and disability among frequently occurring facial pain and the second leading cause of musculoskeletal conditions. AIM: We examined whether acupuncture could alleviate pain intensity in patients with TMD. DESIGN AND METHODS: Sixty participants with TMD were randomly assigned (ratio 1:1) to receive three acupuncture or sham acupuncture sessions weekly for 4 weeks. The primary outcome was the change in the mean weekly pain intensity from baseline to week 4. Secondary and exploratory outcomes included proportion of participants with ≥30% or ≥50% reduction in pain intensity, change in jaw opening and movement, graded chronic pain scale, jaw functional limitations scale-20-item, depression, anxiety and stress scales-21, Pittsburgh sleep quality index at week 4 and 8, and the pressure pain threshold and surface electromyography at week 4. RESULTS AND CONCLUSION: The acupuncture group showed significantly reduced pain intensity compared to the sham group at week 4 (-1.49, 95% confidence interval [CI]: -2.32 to -0.65; P < 0.001) and week 8 (-1.23, 95% CI: -2.11 to -0.54; P = 0.001). Acupuncture's effectiveness surpassed sham's at 4 weeks and lasted 8 weeks. Participants in the acupuncture group experienced significantly greater improvements in the 30% and 50% response rate, jaw opening and movement, GCPS, JFLS-20, DASS-21 and PSQI than those in the sham acupuncture group. There were no significant between-group differences in PPT and sEMG. In summary, acupuncture provided marked pain relief and improvement in physical and emotional function for patients with TMD compared with sham acupuncture.

Lung cancer cell-intrinsic IL-15 promotes cell migration and sensitizes murine lung tumors to anti-PD-L1 therapy.

BACKGROUND: IL-15 plays a vital role in enhancing NK cell- and T-cell-mediated antitumor immune responses; however, the direct effect of IL-15 on tumor cells has not been fully elucidated. Herein, we investigated the effect of IL-15 on lung adenocarcinoma cells. METHODS: Silencing and overexpression techniques were used to modify endogenous IL-15 expression in tumor cells. Transwell assays were used to assess tumor cell migration and invasion; a live-cell analysis system was used to evaluate cell motility; cellular morphological changes were quantified by confocal fluorescence microscopy; the molecular mechanisms underlying the effect of IL-15 on tumor cells were analyzed by western blotting; and RhoA and Cdc42 activities were evaluated by a pulldown assay. NCG and C57BL/6 mouse models were used to evaluate the functions of IL-15 in vivo. RESULTS: Cancer cell-intrinsic IL-15 promoted cell motility and migration in vitro and metastasis in vivo via activation of the AKT-mTORC1 pathway; however, exogenous IL-15 inhibited cell motility and migration via suppression of the RhoA-MLC2 axis. Mechanistic analysis revealed that both the intracellular and extracellular IL-15-mediated effects required the expression of IL-15Rα by tumor cells. Detailed analyses revealed that the IL-2/IL-15Rß and IL-2Rγ chains were undetected in the complex formed by intracellular IL-15 and IL-15Rα. However, when exogenous IL-15 engaged tumor cells, a complex containing the IL-15Rα, IL-2/IL-15Rß, and IL-2Rγ chains was formed, indicating that the differential actions of intracellular and extracellular IL-15 on tumor cells might be caused by their distinctive modes of IL-15 receptor engagement. Using a Lewis lung carcinoma (LLC) metastasis model, we showed that although IL-15 overexpression facilitated the lung metastasis of LLC cells, IL-15-overexpressing LLC tumors were more sensitive to anti-PD-L1 therapy than were IL-15-wild-type LLC tumors via an enhanced antitumor immune response, as evidenced by their increased CD8+ T-cell infiltration compared to that of their counterparts. CONCLUSIONS: Cancer cell-intrinsic IL-15 and exogenous IL-15 differentially regulate cell motility and migration. Thus, cancer cell-intrinsic IL-15 acts as a double-edged sword in tumor progression. Additionally, high levels of IL-15 expressed by tumor cells might improve the responsiveness of tumors to immunotherapies.

Localized Administration of Bcar3 siRNA via Nano-Self-Assembly to Treat Idiopathic Pulmonary Fibrosis by Disrupting Macrophage-Fibroblast Crosstalk.

Background: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by chronic lung injury leading to macrophage infiltration and fibroblast activation. However, there is no effective therapeutic strategy targeting the crucial crosstalk between macrophages and fibroblasts to halt IPF progression. Methods: Studies were conducted in IPF patients and fibrotic mice models to elucidate the role of Bcar3 in the pathogenesis of pulmonary fibrosis. The effect of Bcar3 on macrophage polarization, fibroblast activation, and related signaling pathways were next investigated to unravel the underlying mechanisms. Results: Our study elucidates a marked increase in Bcar3 expression in lung tissues from IPF patients and fibrotic mice, recording 1.7 and 7.8-fold increases compared to control subjects, respectively. Additionally, Bcar3 was found to significantly enhance macrophage activation and fibroblast differentiation, observable in both in vivo and in vitro settings. Mechanistically, the upregulation of Bcar3 in macrophages was reliant on Stat6, while in fibroblasts, it depended on TGFßR1/Smad3. Furthermore, Bcar3 augmented IL-4/Stat6 pathway in macrophages and TGF-ß/Smad3 pathway in fibroblasts, supporting a synergistic activation loop that expedited lung fibrogenesis. Notably, intratracheal injection of liposomes containing Bcar3 siRNA precisely delivered gene therapeutics to lung macrophages and fibroblasts, effectively reducing Bcar3 expression to 59% of baseline levels. Importantly, this intervention protected mice from lung fibrosis induced by either FITC or bleomycin, as well as human precision-cut lung slices against TGF-ß1 stimulation. Conclusion: Our study underscores the pivotal role of Bcar3 in orchestrating the macrophage-fibroblast crosstalk during pulmonary fibrosis progression. Targeting Bcar3 emerges as a novel therapeutic avenue to halt IPF progression and enhance patient prognosis.

Accurate and non-invasive localization of multi-focal ground-glass opacities via electromagnetic navigation bronchoscopy assisting video-assisted thoracoscopic surgery: a single-center study.

Background: Accurate localization of multi-focal ground-glass opacities (GGOs) is crucial for successful video-assisted thoracoscopic surgery (VATS). Electromagnetic navigation bronchoscopy (ENB) provides a minimally invasive and dependable approach for precise localization. This study assessed the accuracy and safety of ENB-guided localization in cases involving multi-focal GGOs. Methods: This retrospective study presents a single-center investigation into ENB-guided localization, utilizing methylene blue, for multi-focal GGOs assisting VATS. Clinical, surgical, and pathological data were collected from patients who underwent ENB-guided localization between 23 December 2019 and 31 August 2022. Results: The study examined 57 patients with multi-focal GGOs who underwent ENB-guided localization and VATS. A total of 150 GGOs were treated, with ENB-guided localization taking a median time of 65 min. Following localization, all patients proceeded to VATS, with a median duration of 170 min. The median lesion size measured 7.8 mm, with a 5-mm distance between GGO and pleura or fissure. When the distance between GGO and pleura/fissure exceeded 1 cm, an additional location point was introduced below the pleura or fissure based on GGO location. No complications related to localization were observed. The overall malignancy rate stood at 66%. Location precision was confirmed by measuring the marker-to-GGO lesion distance, resulting in a 94% (141/150) accuracy rate for GGO localization. Conclusion: ENB-guided methylene blue injection is a safe and precise method to treat multi-focal GGOs, potentially minimizing operation time and simplifying lesion detection.

Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Macrophages, particularly alternatively activated macrophages (M2), have been recognized to contribute to the pathogenesis of pulmonary fibrosis. Therefore, targeting macrophages might be a viable therapeutic strategy for IPF. Herein, we report a potential nanomedicine-based gene therapy for IPF by modulating macrophage M2 activation. In this study, we illustrated that the levels of pleckstrin homology and FYVE domain containing 1 (Plekhf1) were increased in the lungs originating from IPF patients and PF mice. Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation. Mechanistically, Plekhf1 was upregulated by IL-4/IL-13 stimulation, after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis. Therefore, intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis, concomitant with a significant reduction in M2 macrophage accumulation in the lungs. In conclusion, Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis, and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.

TGFß Antagonizes IFNγ-Mediated Adaptive Immune Evasion via Activation of the AKT-Smad3-SHP1 Axis in Lung Adenocarcinoma.

IFNγ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGFß promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGFß inhibits IFNγ signaling in immune cells. We thus sought to determine whether TGFß affects IFNγ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGFß stimulation of tumor cells increased SHP1 phosphatase activity in an AKT-Smad3-dependent manner, decreased IFNγ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion-related molecules, e.g., PD-L1, IDO1, herpes virus entry mediator (HVEM), and galectin-9 (Gal-9). In a lung cancer mouse model, dual blockade of TGFß and PD-L1 led to superior antitumor activity and prolonged survival compared with anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGFß and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared with that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFNγ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGFß on the development of IFNγ-mediated tumor resistance to immunotherapy. SIGNIFICANCE: Blocking TGFß facilitates IFNγ-mediated resistance to anti-PD-L1 therapy due to the role of TGFß in inhibiting IFNγ-induced immunoevasion by increasing SHP1 phosphatase activity in tumor cells.

Ground-glass opacity in a patient with right aortic arch and no left pulmonary artery.

BACKGROUND: Here we report a case of patients with mixed ground glass opacity in the left lung combined with congenital right aortic arch, which is only present in 0.01-0.1% of adults. CASE PRESENTATION: A 60-year-old woman was referred to our department with a mixed ground-glass opacity (GGO) in the upper lobe of her left lung. She had congenital right aortic arch, and the left pulmonary artery was absent. Enhanced chest computed tomography, pulmonary perfusion imaging, and three-dimensional reconstruction were performed to confirm the blood supply in the left lung and the exact location of the GGO. Because of the unusual left pulmonary vascular structure, wedge resection was performed to prevent massive hemorrhage. The final pathological examination revealed that the mixed GGO was a well-differentiated pulmonary adenocarcinoma. CONCLUSION: The surgical options should be evaluated carefully in view of the complications and the prognosis of the patient, when ground glass opacity is combined with congenital cardiovascular anomalies.

Comparative genomics analysis of the multidrug-resistant Aeromonas hydrophila MX16A providing insights into antibiotic resistance genes.

In this paper, the whole genome of the multidrug-resistant Aeromonas hydrophila MX16A was comprehensively analyzed and compared after sequencing by PacBio RS II. To shed light on the drug resistance mechanism of A. hydrophila MX16A, a Kirby-Bauer disk diffusion method was used to assess the phenotypic drug susceptibility. Importantly, resistance against ß-lactam, sulfonamides, rifamycins, macrolides, tetracyclines and chloramphenicols was largely consistent with the prediction analysis results of drug resistance genes in the CARD database. The varied types of resistance genes identified from A. hydrophila MX16A revealed multiple resistance mechanisms, including enzyme inactivation, gene mutation and active effusion. The publicly available complete genomes of 35 Aeromonas hydrophila strains on NCBI, including MX16A, were downloaded for genomic comparison and analysis. The analysis of 33 genomes with ANI greater than 95% showed that the pan-genome consisted of 9556 genes, and the core genes converged to 3485 genes. In summary, the obtained results showed that A. hydrophila exhibited a great genomic diversity as well as diverse metabolic function and it is believed that frequent exchanges between strains lead to the horizontal transfer of drug resistance genes.

Application of electromagnetic navigation bronchoscopy-guided microwave ablation in multiple pulmonary nodules: a single-centre study.

OBJECTIVES: Electromagnetic navigation bronchoscopy (ENB)-guided microwave ablation is a minimally invasive technology for treating pulmonary lesions. This study analysed the short-term safety and efficacy of ENB-guided microwave ablation in multiple pulmonary nodules (MPNs). METHODS: This retrospective study reports a single-centre experience with ENB-guided microwave ablation for MPNs. Clinical, surgical and pathological data were obtained for patients who underwent ENB-guided microwave ablation from 23 December 2019 to 23 June 2021. The primary end points were technical safety and efficiency. RESULTS: The study assessed 65 patients who underwent ENB-guided microwave ablation, 57 of whom simultaneously underwent video-assisted thoracic surgery. In total, 216 nodules were treated. Of 96 nodules treated by ENB-guided microwave ablation, 94 nodules had ground-glass opacity. Ablation efficiency was confirmed by hybrid cone-beam computed tomography. Of 120 nodules surgically removed, 106 nodules had ground-glass opacity. The mean nodule size was 7.9 mm in ablated nodules and 10.2 mm in resected nodules. Distance between nodules and pleura or fissure was 17.45 mm in ablated nodules and 7.29 mm in resected nodules. The overall malignancy rate was 47.7% (103/216); the complication rate was low (65 patients). At short-term follow-up, the post-ablation target zone shrank by 1 week and stabilized after 4-6 months. No local recurrence or enlargement of other pulmonary nodules was noted. CONCLUSIONS: To treat MPNs, ENB-guided microwave ablation is safe and efficient. The combination of this treatment and video-assisted thoracic surgery is a potential application, which can preserve as much pulmonary function as possible and treat MPNs to the maximum extent.

An IFNγ/STAT1/JMJD3 Axis Induces ZEB1 Expression and Promotes Aggressiveness in Lung Adenocarcinoma.

Active IFNγ signaling is a common feature of tumors responding to PD-1 checkpoint blockade. IFNγ exhibits both anti- and protumor activities. Here, we show that the treatment of lung adenocarcinoma cells with IFNγ led to a rapid increase of ZEB1 expression and a significant change in epithelial-to-mesenchymal transition (EMT)-associated gene expression pattern. Moreover, functional analyses show that IFNγ promoted cell migration in vitro and metastasis in vivo. We demonstrate that ZEB1 is required for IFNγ-promoted EMT, cell migration, and metastasis, as RNAi-mediated knockdown of ZEB1 abrogated EMT, cell migration, and metastasis induced by IFNγ. We show that IFNγ induced upregulation of JMJD3 significantly reduced H3K27 trimethylation in the promoter of the ZEB1 gene, which led to activation of ZEB1 gene transcription. IFNγ-induced JMJD3 expression was JAK1/2-STAT1 dependent. Inhibition of JMJD3 abrogated IFNγ-induced ZEB1 expression. IFNγ-induced ZEB1 also reduced miR-200 expression. Downregulation of ZEB1 increased miR-200 expression, which led to a reduction of PD-L1 expression induced by IFNγ. It is worth noting that knockdown of ZEB1 did not affect IFNγ-mediated antiproliferation and induction of CXCL9 and CXCL10. Thus, downregulation of ZEB1 may prevent the protumor activity of IFNγ while retaining its antitumor function. This study expands our understanding of IFNγ-mediated signaling and helps to identify therapeutic targets to improve current immunotherapies. IMPLICATIONS: IFNγ increases ZEB1 expression in a STAT1-JMJD3 dependent manner, and consequently promotes cancer cell aggressiveness. This study provides a potential target to minimize the procancer effect of IFNγ while preserving its antitumor function.

Thermal Ablation Versus Wedge Resection for Stage I Non-small Cell Lung Cancer Based on the Eighth Edition of the TNM Classification: A Population Study of the US SEER Database.

BACKGROUND: The incidence rates of early-stage non-small cell lung cancer (NSCLC) are now increasing, and therapies such as thermal ablation have shown potential therapeutic promise. This study aimed to determine the influence of different surgical methods on overall survival (OS) and cancer-specific survival (CSS) in patients with stage I NSCLC. METHODS: Patients diagnosed with stage I NSCLC who had received thermal ablation or wedge resection between 2004 and 2014 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed according to the surgical method. Kaplan-Meier curves and a Cox proportional hazard model were used to evaluate OS and CSS. RESULTS: In all, 4,372 patients with stage I NSCLC were included. Before PSM, the respective 3- and 5-year OS rates were 68.9 and 52.7% in the wedge resection group and 68.5 and 47.8% in the thermal ablation group (p < 0.0001); the corresponding CSS rates were 79.1 and 69.4% and 62.6 and 46.0% (p < 0.0001). After PSM, survival analysis showed that wedge resection had better OS (44.5% vs. 30.1%, p = 0.033) and CSS (63.5% vs. 46%, p = 0.038) than thermal ablation. After PSM, Cox regression showed that treatment was not associated with OS or CSS. For patients aged >75 years, thermal ablation showed similar OS and CSS as wedge resection (OS: 30.6% vs. 41.7%, p = 0.470; CSS: 46.4% vs. 64.1%, p = 0.100). After PSM, thermal ablation still had OS (30.6% vs. 41.0%, p = 0.470) and CSS (46.4% vs. 59.8%, p = 0.100) comparable to wedge resection. CONCLUSION: For patients with stage I NSCLC who are unfit for lobectomy, thermal ablation could be a potential therapeutic option, especially for those >75 years old.

Tumor-infiltrating CD8+ T cells in ALK-positive lung cancer are functionally impaired despite the absence of PD-L1 on tumor cells.

Several lines of evidence have demonstrated that programmed cell death 1 (PD-1) inhibitors as monotherapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer have little clinical activity. The underlying mechanisms remain not understood. In this study, using immunohistochemistry and in situ RT-PCR assays, we examined the expression of programmed cell death ligand 1 (PD-L1), PD-1, CD8, and interferon gamma (IFN-γ) in tumors. Both epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-positive tumors were associated with low or absent membrane PD-L1 expression. Interestingly, unlike EGFR-mutant tumors with few tumor-infiltrating CD8+ T cells, a significant number of PD-1-positive CD8+ T cells infiltrated the ALK-positive tumor bed; however, these cells did not express IFNG mRNA. These results demonstrate that the ALK-positive tumor microenvironment suppresses the immune function of tumor-infiltrating CD8+ T cells through a PD-1/PD-L1-independent mechanism, which might lead to the inability of ALK-positive tumors to respond to PD-1/PD-L1-based immunotherapy.

Pulmonary contusion during the COVID-19 pandemic: challenges in diagnosis and treatment.

Managing patients with pulmonary contusion safely and effectively during the coronavirus disease 2019 (COVID-19) pandemic is challenging. This retrospective study analyzes the clinical data of 29 consecutive patients with pulmonary contusion, including two with COVID-19, at Tongji Hospital, Wuhan, China, in January and February, 2020. We analyzed the clinical manifestations, laboratory test results, computed tomography (CT) images, treatment, and clinical outcomes. The two patients with pulmonary contusion and COVID-19 had increased leukocyte and neutrophil counts, similar to the patients with pulmonary contusion alone. Interestingly, both these patients had subpleural ground glass opacity on CT images as a typical manifestation of COVID-19. All 29 patients were treated conservatively, including with closed thoracic drainage, instead of with thoracotomy. Six patients died of ARDS or craniocerebral injury, but the others stabilized. During the COVID-19 pandemic, patients with pulmonary contusion should be tested for SARS-CoV-2 and unless critical, thoracotomy should be avoided.

IL-10 suppresses IFN-γ-mediated signaling in lung adenocarcinoma.

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by a wide variety of cells. It has been implicated in cancer progression, and at times, it has seemingly contradictory effects. The impact of IL-10 on immune components in the context of cancer has been intensively investigated, but its effect on cancer cells remains poorly understood. In this study, we examined the expression of IL-10 and IL-10 receptor 1 (IL-10R1) in resected locally advanced lung adenocarcinoma by immunohistochemistry. IL-10 immunoreactivity was stronger in intraepithelial regions than in stroma. The amount of IL-10 found either in intraepithelial or in stromal regions had no prognostic value, but the relative distribution of IL-10 in these two locations was related to cancer-immune phenotypes. High expression of IL-10R1 by tumor cells was significantly correlated with poor prognosis, suggesting that IL-10-mediated signaling may induce cancer cell intrinsic effects that promote cancer progression. Functional analysis using human lung adenocarcinoma cell lines revealed that IL-10 did not directly affect cell proliferation and migration. Incubation of cancer cells with IL-10 suppressed interferon-γ (IFN-γ)-induced STAT1 phosphorylation and inhibited the transcription of IFN-γ-targeted genes, such as CXCL9, CXCL10, and PD-L1. IL-10 enhanced IFN-γ-induced SOCS1 and SOCS3 expression, an effect that might be responsible for the downregulation of STAT1 activity in cancer cells. Our findings provide a rationale for targeting IL-10 on cancer cells as a potential strategy for treating cancer.

Comparative analysis of the composition and function of fecal-gut bacteria in captive juvenile Crocodylus siamensis between healthy and anorexic individuals.

The Siamese crocodile (Crocodylus siamensis) is a freshwater, endangered crocodile with high economic value in the farming industry. Gut microflora plays an essential role in host physiological activity, and it contributes significantly to both the health and diseased states of animals. However, thus far, no study has focused on the correlation between diseases and intestinal bacterial communities in crocodilians. Here, we first compared the composition and function of gut microbial communities in captive juvenile C. siamensis suffering from anorexia and healthy crocodile controls using deep amplicon sequencing. The gut microbial diversity of anorexic crocodiles was much lower than the healthy individuals. Obvious changes in gut microbial composition were observed between sick and healthy crocodiles, except for Cetobacterium somerae of phylum Fusobacteria. In particular, the abundance of Bacteroides luti, Clostridium disporicum, Plesiomonas shigelloides, and Odoribacter sp. in the gut flora of healthy crocodiles was distinctly higher than the diseased group. Conversely, the species Edwardsiella tarda was overrepresented in the gut of anorexic crocodiles compared to the healthy group. Furthermore, in anorexic crocodiles, the predicted microbial functions that were related to amino acid metabolism, biosynthesis of other secondary metabolites, nucleotide metabolism, replication and repair, and translation were significantly reduced, while signal transduction was significantly enriched. These findings of the present study provide a reference to enrich the field of gut microorganism studies in crocodilians and suggest that alterations in the composition and function of gut bacteria in C. siamensis juveniles may be associated with anorexia in crocodiles.